This proposal utilizes the unique resources of Mayo Clinic and the Rochester Epidemiology Program Project (REPP) to conduct a retrospective incidence cohort study to assess breast cancer risk among women with benign breast disease. By integrating the histopathologic evaluation capabilities of Mayo Clinic and the population-based epidemiologic data provided by the REPP, this research will provide a detailed assessment of the risk of breast cancer associated with specific histologically defined subcategories of proliferative benign breast disease. The study pathologist will collaborate with Dr. Page to ensure that the Page-Dupont criteria are applied to the breast tissue pathologic slides. Breast tissue from an estimated (9,000) women in the Olmsted County community and at Mayo Clinic from 1/1/67- 1/1/83 will be evaluated histopathologically with these criteria, and this retrospective incidence cohort will be followed for occurrence of breast cancer to 1/1/88. Using breast cancer cases and a matched control group from this cohort, a nested biopsy from medical records of these patients. In addition, DNA flow cytometry and immunohistochemistry will be conducted on benign breast disease tissue from cases and controls. The combined clinical, epidemiologic, flow cytometric, and histopathologic data will be used to evaluate the interaction between these factors and breast cancer risk. Previous REPP research concerned with the relationship between benign breast lesions and subsequent breast cancer affirms the ability of this data source to identify the relevant study population. Ongoing participation in the DES- breast cancer studies verifies the ability to determine the appropriate clinical and epidemiologic parameters and to provide nearly 100% follow-up for breast cancer occurrence to 1/1/88 in this (9,000) member benign breast disease incidence cohort. More than 300 cases of breast cancer are anticipated in this cohort which should provide adequate power to detect clinically and statistically important relationships of interest. Comparisons between the Olmsted County cohort and the non-Olmsted County Mayo Clinic referral cohort will provide a unique opportunity to determine the influence of referral bias on the epidemiology of benign breast disease. This study will, therefore, assess the predictive validity of the Page-Dupont criteria and determine if additional clinical, epidemiologic, flow cytometric, or histopathologic factors improve the precision of risk assessment.